Cholesterol metabolism drives regulatory B cell IL-10 through provision of geranylgeranyl pyrophosphate

Abstract

Regulatory B cells restrict immune and inflammatory responses across a number of contexts. This capacity is mediated primarily through the production of IL-10. Here we demonstrate that the induction of a regulatory program in human B cells is dependent on a metabolic priming event driven by cholesterol metabolism. Synthesis of the metabolic intermediate geranylgeranyl pyrophosphate (GGPP) is required to specifically drive IL-10 production, and to attenuate Th1 responses. Furthermore, GGPP-dependent protein modifications control signaling through PI3Kδ-AKT-GSK3, which in turn promote BLIMP1-dependent IL-10 production. Inherited gene mutations in cholesterol metabolism result in a severe autoinflammatory syndrome termed mevalonate kinase deficiency (MKD). Consistent with our findings, B cells from MKD patients induce poor IL-10 responses and are functionally impaired. Moreover, metabolic supplementation with GGPP is able to reverse this defect. Collectively, our data define cholesterol metabolism as an integral metabolic pathway for the optimal functioning of human IL-10 producing regulatory B cells.

Effects of short-chain fatty acids in inhibiting HDAC and activating p38 MAPK are critical for promoting B10 cell generation and function

“…It has been reported that Prdm1 promotes IL-10 expression in B cells 21 when stimulated with CpG, while Prdm1-deficient mice have more IL-10 + B cells 22 . Butyrate hinders B cell differentiation into plasmablasts 20 , in which Prdm1 plays a vital role 23 .…”

Immunosuppressive Mechanisms of Regulatory B Cells

“…Transcriptional analyses of human activated IL-10 + B cells have found, as for mouse, the upregulation of genes coding for molecules involved in plasma cell differentiation, such as Blimp-1 and IRF4, thus confirming that human IL-10 + B cells are also capable of becoming ASCs ( 12 , 17 , 19 , 57 ). Interestingly, it has been suggested that human and mouse IL-10-producing ASCs can be differentiated directly from immature and naïve B cells ( 15 , 55 ), which is supported by the finding that Blimp-1 is already expressed in recently activated naïve B cells ( 58 , 59 ).…”

“…STAT3 phosphorylation is increased in CD40-activated transitional B cells of healthy subjects but not in those from SLE patients ( 26 ). In addition, CREB, p38 MAPK, ERK1/2, and PI3Kδ have been described to be required for IL-10 upregulation following TLR and/or CD40L stimulation ( 58 , 67 , 110 ). c-Maf, a well-known transactivator of IL-10 in various cell types, has also been shown to mediate IL-10 transcription by LPS-stimulated murine B cells ( 111 ).…”

“…Furthermore, free fatty acid palmitate can increase survival and IL-10 synthesis by adipose tissue-resident B cells, suggesting a potential participation of lipid metabolism in Breg functions ( 125 ). Accordingly, a publication has recently described that atorvastatin, an inhibitor of cholesterol metabolism, prevents IL-10 production by CpG-activated B cells through reducing geranylgeranyl pyrophosphate-mediated activation of Akt and inhibition of GSK3β, leading to a decreased transcription of Blimp-1 and IL-10 ( 58 ). The metabolic regulation of B cell responses is an emerging field that would offer new insights into the factors that govern the fate of activated B cells, including Bregs.…”

How Changes in the Nutritional Landscape Shape Gut Immunometabolism

“…Similarly, protein prenylation was shown to limit hyper-production of proinflammatory cytokines as well as constitutive activation of pyrin inflammasome in macrophages [ 76 ]. The anti-inflammatory effects of protein prenylation extend to other cell subsets such as B cells by inducing their production anti-inflammatory IL-10 thus promoting anti-inflammatory regulatory B cell differentiation [ 81 ].…”